Compositions and methods comprising osmium for the treatment of cancers

Abstract

Compositions and methods comprising osmium are provided. In some embodiments, the osmium compounds comprise a bidentate ligand. In some embodiments, the osmium compounds are used in method for treating cancer.

What is claimed is: 
     
       1. A composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , and X 3  are the same or different and are selected from the group consisting of halo, —CN, —OR′, —OCN, —SeCN, —SR′, —SCN, —OCOR′, —OSO 2 , and —OPO 3 R′ 2 ; 
 each R′ is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and 
 
       
         
           
           
               
               
           
         
       
       is a bidentate ligand comprising the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently —CN, —OR 3 , —SR 3 , —COOR 3 , —OCOR 3 , —N(R 3 ) 2 , —NO 2 , halo, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloheteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally any two R 1  may be joined to form a ring; 
 each R 3  is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each e is independently 0, 1, 2, 3, 4, or 5; 
 each p is independently 0, 1, 2, or 3; and 
 each a is independently 0, 1, or 2 
 
       wherein at least one R 1  is substituted with -Q, wherein -Q is a targeting moiety. 
     
     
       2. The composition of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       comprises the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1  is independently —CN, —OR 3 , —SR 3 , —COOR 3 , —OCOR 3 , —N(R 3 ) 2 , —NO 2 , halo, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloheteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted heteroaryl, or optionally any two R 1  may be joined to form a ring; 
 each R 3  is independently hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each e is independently 0, 1, 2, 3, 4, or 5; 
 each p is independently 0, 1, 2, or 3; and 
 each a is independently 0, 1, or 2. 
 
     
     
       3. The composition of  claim 1 , wherein at least one R 1  is substituted with -L-Q, wherein L is a linking moiety and Q is a targeting moiety. 
     
     
       4. The composition of  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       comprises the structure: 
       
         
           
           
               
               
           
         
         wherein L is a linking moiety and Q is a targeting moiety. 
       
     
     
       5. The composition of  claim 1 , wherein X 1 , X 2 , and X 3  are halo. 
     
     
       6. The composition of  claim 1 , wherein X 1 , X 2 , and X 3  are chloro. 
     
     
       7. The composition of  claim 1 , wherein R′ is optionally substituted alkyl or optionally substituted aryl. 
     
     
       8. The composition of  claim 4 , wherein L is three hydrophobic amino acids, each independently selected from the group consisting of alanine, valine, isoleucine phenylalanine, tryptophan, and tyrosine. 
     
     
       9. The composition of  claim 4 , wherein Q is a peptide. 
     
     
       10. The composition of  claim 1 , wherein the compound causes at least a two-fold increase in cell death in a cancer cell compared to a non-cancer cell. 
     
     
       11. The composition of  claim 1 , wherein the compound causes at least a two-fold increase in cell death in cancer stem cells compared to non-cancer cells. 
     
     
       12. The composition of  claim 1 , wherein the compound causes at least a two-fold increase in cell death in cancer stem cells compared to cancer cells. 
     
     
       13. A pharmaceutical composition, comprising:
 the compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and 
 one or more pharmaceutically acceptable carriers, additives, and/or diluents. 
 
     
     
       14. A kit for the treatment of cancer, comprising:
 the composition of  claim 1 ; and 
 instructions for use of the composition for treatment of cancer. 
 
     
     
       15. A method of treating cancer in a patient in need of treatment for cancer, comprising:
 administering the composition of  claim 1  to the patient. 
 
     
     
       16. The composition of  claim 1 , wherein the compound has a log P greater than or equal to about 1.7.